Transdermal patch incorporating active agent migration barrier layer

ABSTRACT

Devices for administration of one or more active agents to the skin or mucosa of a host are formed in the nature of a double-disk patch. One outer layer functions as the primary adhesive layer for adhering the patch to the host. The other inner layer contains at least one active agent to be administered to the host. The inner layer is bonded to the outer layer through an opening provided in an interposed active agent impermeable release layer. The release layer separates a circumferential portion of the active agent containing inner layer from the outer adhesive layer to inhibit migration of the active agent therebetween.

FIELD OF THE INVENTION

The present invention relates in general to a device for the release ofan active agent to be administered to the skin or mucosa of a host. Moreparticularly, the present invention relates to transdermal patches whichinhibit active agent migration by incorporating a releasable barrierlayer.

BACKGROUND OF THE INVENTION

The use of transdermal patches for the delivery of various drug systemshas met with increasing success in the pharmaceutical industry,particularly in view of specific problems which have arisen inconnection with drugs taken by other means, and because of theirimplications in terms of long term application of drugs in a particularsimple manner. One of the specific problems which has been encounteredin connection with the use of various drugs has been the ability toapply a drug in a simple system which employs the drug in admixture withan adhesive base system for application to the skin, or non-adhesivebase system having an outer drug permeable adhesive layer. The abilityto do this with various types of drugs can be impeded by variousconsiderations, such as differences in viscocity, solubility,therapeutic drug delivery rate, drug migration within the system, andthe like.

Simple monolithic transdermal systems incorporate their active agents,i.e., drugs, directly into a single pressure sensitive adhesive layer.These systems have the advantage of being thin, elegant, and relativelyeasy to manufacture, but must compromise between optimizing the adhesivematrix for drug delivery versus its ability to adhere to the skin.

The known “double-disk” transdermal patch uses a larger auxiliary patchover a smaller active agent delivery patch to improve or ensure adhesionto the skin. The adhesive matrixes of the inner and outer patches can beindependently optimized for active agent delivery and adhesion,respectively. When the inner and outer patches are laminated together toform the completed system, their adhesive matrixes come into directcontact and begin to equilibrate. As the systems equilibrate,time-dependent changes occur such as the loss of active agents from theinner patch and the simultaneous accumulation of active agents in theouter patch. This phenomena can alter the performance of the transdermalpatch if any of the components in the inner patch, especially those thatare needed to achieve or sustain active agent delivery, have appreciableaffinity for the outer patch adhesive matrix. Moreover, this effect willbecome more profound with time until equilibrium is achieved.

One solution in preventing the equilibrium of the two adhesive matrixesis to maintain their physical separation, and not to allow the adhesivesto come into direct contact with each other during storage. Followingapplication to the skin, these adhesive matrixes will be in directcontact, but the equilibrium process, typically two-three years, is slowcompared to the transdermal delivery process, generally less than sevendays. However, in the double-disk transdermal patch, the circumferentialedge of the inner patch containing the active agent is exposed to theoverlying outer patch and its adhesive matrix. This structure of thedouble-disk transdermal patch allows for the circumferential migrationof active agent from the inner patch into the adhesive matrix of theouter patch.

SUMMARY OF THE INVENTION

The device of the present invention inhibits the migration of activeagents between the inner and outer patches by maintaining a physicalbarrier between the patches during storage, i.e., prior to use by apatient. This allows the device to overcome the material compatibilitylimitations previously associated with double-disk type transdermalpatches. Although the device of the present invention has specificapplication in transdermal patches, the device has general applicationfor the release of an active agent to the skin or mucosa of a host. Inthis regard, the device has application in active agent delivery systemswhich include, but are not limited to, transmucosal, buccal, sub-lingualand medicated wound care.

The device of the present invention more broadly inhibits the migrationof a component of the device, such as both active and non-active agentsand other ingredients, including but not limited to non-activeexcipients, penetration enhancers, plasticizers, etc. between the innerand outer patches of the devise. In this regard, components included inthe device of the present invention are inhibited from migration fromthe outer patch into the inner patch and from the inner patch into theouter patch.

The device of the present invention adheres the inner and outer patchesin a manner to create an annular flap circumferentially about the outerportion of the inner patch. A disposable release liner is interposedbetween the annular flap and the adhesive material of the outer patch.The annular flap containing the active agent is isolated from theunderlying portion of the outer patch by the release liner to inhibitactive agent migration therebetween.

More specifically, the device of the present invention is in the natureof a double-disk system which includes an active agent containing innerpatch permanently attached to an adhesive outer patch through an openingprovided in a release liner for the outer patch. The inner patchincludes an active agent impermeable backing layer, active agent layercontaining the active agent to be delivered to the skin or mucosa of ahost, which may also be an adhesive matrix layer and a disposablerelease liner. The outer patch includes a backing layer, adhesive matrixlayer which may contain additional active agents, and a disposablerelease liner preferably of active agent impermeable material. Theopening in the release liner of the outer patch exposes a portion of theouter patch adhesive matrix. The opening is smaller in size than theactive agent inner patch, and provides an anchor point for the innerpatch while preventing contact between the inner and outer patches priorto use.

In one embodiment of the present invention there is described a devicefor the release of an active agent to the skin or mucosa of a host, thedevice comprising an outer layer having adhesive properties; an innerlayer having an active agent impermeable layer, the inner layer having aportion thereof adhered to the outer layer; and a release linerinterposed between a portion of the impermeable layer and a portion ofthe outer layer, whereupon removal of the release liner exposes theouter layer for adhering the device to the skin or mucosa of a host.

In a further embodiment of the present invention there is described adevice for the release of an active agent to the skin or mucosa of ahost, the device comprising a first layer having adhesive propertiesadapted for adhering said first layer to the skin or mucosa of a host; asecond layer releasably adhered to the first layer, the second layerhaving an opening exposing a portion of the first layer; and a thirdlayer overlying the second layer, the third layer including an activeagent impermeable layer having a portion thereof adhered to the firstlayer within the opening in the second layer, the second layerseparating a portion of the third layer from the first layer prior toremoval of the second layer when adhering the device to the skin ormucosa of a host by the first layer.

In a further embodiment of the present invention there is described adevice for the release of an active agent to the skin or mucosa of ahost, the device comprising an outer layer having top and bottomsurfaces, the top surface of the outer layer having adhesive propertiesadapted for adhering the outer layer to the skin or mucosa of a host; aliner releasably adhered to the top surface of the outer layer, theliner having an opening exposing a portion of the top surface of theouter layer; an active agent inner layer having an active agentoverlying the liner, the inner layer having a surface area smaller thana surface area of the outer layer and greater than a surface area of theopening in the liner; and an active agent impermeable layer adhered tothe bottom surface of the inner layer, the impermeable layer having aportion thereof adhered to the top surface of the outer layer within theopening in the liner, whereby a portion of the liner is interposedbetween a portion of the inner layer and a portion of the outer layer toinhibit migration of the active agent from the inner layer to the outerlayer prior to adhering the device to the skin or mucosa of a host uponremoval of the liner.

In a further embodiment of the present invention there is described amethod for inhibiting migration of a component of an active agentrelease device between an inner layer and an adhesive outer layer withinthe device prior to adhering the device to the skin or mucosa of a host,the inner layer having a component impermeable layer partially adheredto the outer layer, the method comprising interposing a release linerbetween a peripheral portion of the inner layer and the outer layer.

In a further embodiment of the present invention there is described amethod for inhibiting migration of an active agent from an active agentinner layer into an adhesive outer layer within an active agent releasedevice prior to adhering the device to the skin or mucosa of a host, theinner layer having an active agent impermeable layer, the methodcomprising adhering a release liner to a first portion of the outerlayer; and adhering a portion of the impermeable layer of the innerlayer to a second portion of the outer layer, whereby a remainingportion of the impermeable layer is arranged overlying the releaseliner, the release liner separating a peripheral portion of the innerlayer from the outer layer until removal of the release liner.

In a further embodiment of the present invention there is described amethod of making a device for the release of an active agent to the skinor mucosa of a host, the method comprising adhering a portion of anactive agent impermeable layer of an inner layer to an outer layerhaving adhesive properties; and interposing a release liner between aportion of the impermeable layer and the outer layer, whereupon removalof the release liner exposes the outer layer for adhering the device tothe skin or mucosa of a host.

In a further embodiment of the present invention there is described amethod of making a device for the release of an active agent to the skinor mucosa or a host, the method comprising providing a first layerhaving adhesive properties adapted for adhering the first layer to theskin or mucosa of a host; releaseably adhering a second layer to thefirst layer, the second layer having an opening exposing a portion ofthe first layer; overlying a third layer with the second layer, thethird layer including an active agent impermeable layer; and adhering aportion of the impermeable layer to the first layer within the openingin the second layer, the second layer separating a portion of the thirdlayer from the first layer prior to removal of the second layer whenadhering said device to the skin or mucosa of a host by the first layer.

In a further embodiment of the present invention there is described amethod of making a device for the release of an active agent to the skinor mucosa of a host, the method comprising providing an outer layerhaving top and bottom surfaces, the top surface of the outer layerhaving adhesive properties adapted for adhering the outer layer to theskin or mucosa of a host; releasably adhering a liner to the top surfaceof the outer layer, the liner having an opening exposing a portion ofthe top surface of the outer layer; positioning an active agent innerlayer having an active agent impermeable layer overlying the liner, theinner layer having a surface area smaller than a surface area of theouter layer and greater than a surface area of the opening in the liner;and adhering a portion of the impermeable layer to the top surface ofthe outer layer within the opening in the liner, whereby a portion ofthe liner is interposed between a portion of the inner layer and aportion of the outer layer to inhibit migration of the active agent fromthe inner layer to the outer layer prior to adhering the device to theskin or mucosa of a host upon removal of the liner.

In a further embodiment of the present invention there is described amethod for inhibiting migration of a component of an active agentrelease device between an inner layer and an adhesive outer layer withinthe device prior to adhering the device to the skin or mucosa of a host,at least one of the inner layer and the outer layer including thecomponent, the inner layer having a component impermeable layerpartially adhered to the outer layer within a bonding region, the methodcomprising interposing a release liner between a peripheral portion ofthe inner layer surrounding the bonding region and the outer layer.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with features, objects, and advantages thereof may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1 is a perspective unassembled exploded view of the components of adevice for the release of an active agent for application to the skin ormucosa of a host in accordance with one embodiment of the presentinvention;

FIG. 2 is an assembled cross-sectional view of the device shown in FIG.1;

FIG. 3 is a top plan view of the device shown in FIG. 1;

FIG. 4 is a cross-sectional view of the application of the device shownin FIG. 2 adhered to the skin or mucosa of a host;

FIG. 5 is a perspective unassembled exploded view of the components of adevice for the release of an active agent for application to the skin ormucosa of a host in accordance with another embodiment of the presentinvention;

FIG. 6 is an assembled cross-sectional view of the device shown in FIG.5;

FIG. 7 is a top plan view of the device shown in FIG. 6; and

FIGS. 8-10 are diagrammatic illustrations of one embodiment a method offorming devices in accordance with the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In describing the preferred embodiments of the invention illustrated inthe drawings, specific terminology will be used for the sake of clarity.However, the invention is not intended to be limited to the specificterms so selected, and it is to be understood that each specific termincludes all technical equivalents that operate in a similar manner toaccomplish a similar purpose.

Referring now to the drawings, wherein like elements represent likeelements, there is shown in FIG. 1 the unassembled components of adevice for the administration of one or more active agents to the skinor mucosa of a host in accordance with one embodiment of the presentinvention. The device 100 generally includes an outer patch 102, anouter patch release layer 104, an inner patch 106 and an inner patchrelease layer 108. The outer and inner patches 102, 106 and releaselayers 104, 108, which are typically planar layers, are assembled to oneanother to form a laminate composite structure in the nature of a doubledisk device as to be described hereinafter.

The outer patch 102 includes a flexible adhesive layer 110 and aco-extensive protective backing layer 112 adhered thereto. The adhesivelayer 110 provides the primary adhesion of the device 100 to the skin ormucosa of a host. Preferably, the adhesive layer 110 is apressure-sensitive adhesive suitable for contact with the skin or mucosaof a host, e.g., dermatologically acceptable. Optionally, the adhesivelayer may be admixed with an active agent or other drug to beadministered to a host. In which case, the adhesive layer 110 will beformed from active agent permeable material to allow administration ofthe active agent.

The backing layer 112 is preferably a thin sheet which is co-extensivewith the bottom surface of the adhesive layer 110. Because of the areaof skin to which the device 100 is to be attached, the backing layer 112may be flesh-colored for cosmetic reasons. The backing layer 112normally provides support and a protective covering for the device 100.The backing layer 112 may be formed from a sheet of active agentimpermeable or permeable material. Preferably, the backing layer 112will be formed from active agent impermeable material when an activeagent is present in the adhesive layer 110.

The outer patch release layer 104 covers the top surface of the adhesivelayer 110 prior to use of the device 100 to protect the adhesive layerfrom inactivation by ambient dust or other contaminants and to providean active agent migration barrier as to be described. The release layer104 has a sufficient surface area and shape to extend at least to theperipheral edges of the adhesive layer 110. An opening 114 within therelease layer 104 exposes a portion of the top surface of the adhesivelayer 110 of the underlying outer patch 102. The release layer 104 maybe formed as a single sheet of material, or multiple sections 116, 118which are separated by one or more slits 120. Preferably, the releaselayer 104 is formed from a sheet of active agent impermeable materialthereby providing a migration barrier to the active agents in the innerpatch 106.

The inner patch 106 includes a flexible active agent layer 122 and aco-extensive active agent impermeable backing layer 124 adhered to thebottom surface thereof. The active agent layer 122 may be formed from athermoplastic polymeric matrix which is admixed with the active agent ordrug components, and optionally, an active agent enhancer. The polymericmatrix for the active agent layer 122 preferably has pressure-sensitiveadhesive properties, or in the alternative, the active agent layer maybe coated with an active agent permeable adhesive layer 126 as shown inphantom. It is not a requirement of the present invention that theactive agent layer 122 have adhesive properties or be provided with anadhesive layer. In this regard, the device 100 will be adhered to thehost primarily by the adhesive layer 110 of the outer patch 102. Theactive agent layer 122, when having adhesive properties, will add to theadhesion of the device 100 to a host.

The inner patch release layer 108 may be formed as a similar sheet asrelease layer 104 from one or more sections 128, 130 separated by a slit132. The release layer 108 has a surface area and shape to at leastextend to the perimeter of the top surface of the active agent layer122. The release layer 108 covers the top surface of the active agentlayer 122 prior to use of the device 100 to prevent the release of theactive agent. When the active agent layer 122 has pressure-sensitiveadhesive properties, or is covered with an active agent permeableadhesive layer, the release layer 108 provides protection frominactivation by ambient dust or other contaminants.

The device 100 is shown in assembled relationship in FIGS. 2 and 3 inthe nature of a laminate composite device of generally planar layers.The release liner 104 is releasably adhered in co-extensive contact withthe top surface of adhesive layer 110 of the outer patch 102. Theopening 114 in release layer 104 exposes a portion of the top surface ofthe underlying adhesive layer 110. The inner patch 106 is adhered to theouter patch 102 by bonding the impermeable backing layer 124 to theadhesive layer 110 exposed within the opening 114. The surface area ofthe opening 114 is smaller than the surface area of inner patch 106.This results in the inner patch 106 having an annular portion in thenature of a flap surrounding opening 114, which is not bonded to theadhesive layer 110 as a result of an interposed portion of the releaseliner 104. Likewise, the peripheral edges of the active agent layer 122are separated from the adhesive layer 110 by a portion of the releaseliner 104. The impermeable backing layer 124 and impermeable releaselayer 104 isolate the active agent layer 122 to inhibit migration of anactive agent from the active agent layer to the adhesive layer 110during storage of the device 100 prior to use.

The device 100 is prepared for application to the skin or mucosa of ahost by removing release layers 104, 108. To facilitate removal ofrelease layer 104, it is preferable that at least a portion of therelease layer extend beyond the periphery of the underlying adhesivelayer 110. The extended portion may be in the nature of a tab or annularportion circumscribing the entire perimeter or portion of the adhesivelayer 110 as shown in FIG. 3. In this manner, each section 116, 118 ofthe release layer 104 may be removed to expose the top surface of theadhesive layer 110 surrounding the inner patch 106 containing the activeagent. The exposed surface portion of the adhesive layer 110 will havesufficient surface area to provide adhesion of the device 100 to theskin or mucosa of a host during use. Removal of the sections 116, 118are undertaken individually as a result of their separation by slit 120.This enables removal of the sections 116, 118 notwithstanding a portionof the sections surrounding the opening 114 being interposed between theadhesive layer 110 and impermeable backing layer 124 of the inner patch106.

In a like manner, the release layer 108 is removed from the top surfaceof the active agent layer 122 by grasping an extended portion ofsections 128, 130. The device 100 is adhered to the skin or mucosa of ahost 134 as shown in FIG. 4 with the active agent layer 122 in contactwith the host. The host to which an active agent is administered bymeans of the inventive device may be any host on which a drug or otheractive agent has the desired effect. The host may be, for example, amammal such as a human being, or, for that matter, any warm-blooded orcold-blooded animal. The advantage of administering the active agent maybe therapeutic or experimental. The device 100 of this invention mayalso be used for any other advantageous purpose.

The extended sections of the release layer 108 may be as described withrespect to release layer 104. However, it is to be understood that it isnot required that the release layers 104, 108 extend beyond theperiphery of their underlying adhesive layer 110 and active agent layer122, respectively. The extension of the release layers 104, 108 merelyfacilitates removal of the release layers by the user prior toapplication of the device 100.

The individual components of the device 100 have been illustrated asbeing rectangular in shape for illustrative purposes only. It is to beunderstood that the device 100 and its components may have any othershape, such as square, round, oval and the like. For example, the outerpatch 102 may have a square shape, while the inner patch 106 may becircular. In addition, it is not a requirement of the present inventionthat opening 114 be rectangular, and may be formed as a plurality ofnon-contiguous openings within the release layer 104. The opening 114serves one function of enabling bonding of the inner patch 106 to theouter patch 102 in assembling the device 100. In addition, the surfacearea of opening 114 in relationship to the surface area of the innerpatch 108 defines the extent of the circumferential portion of the innerpatch which is separated from the adhesive layer 110 by the interposedrelease layer 104. Accordingly, the size, shape and location of theopening 114 can be tailored to accommodate the migration of an activeagent based upon, for example, the migration rate of the active agentwithin the active agent layer 122.

Referring to FIGS. 5-7, there is disclosed another embodiment of adevice 136 adapted for the administration of an active agent to the skinor mucosa of a host. The device 136 differs in one aspect from thedevice 100 in the shape of its component parts. In this regard, thedevice 106 includes a circular outer patch 138, a square or rectangularouter patch release layer 140, a circular inner patch 142 and a circularinner patch release layer 144.

The outer patch 138 includes an adhesive layer 146 and a co-extensiveouter backing layer 148. The adhesive layer 146 may be in the nature ofa pressure-sensitive adhesive, and optionally, admixed with an activeagent or other drug to be administered to a host. In this event, thebacking layer 148 will be in the nature of a sheet of active agentimpermeable material.

The release layer 140, like release layer 104, is preferably formed froma sheet of active agent impermeable material which is releasably adheredto the top surface of the adhesive layer 146 of the outer patch 138. Therelease layer 140 includes an opening 150 which exposes a portion of thetop surface of the adhesive layer 146 through which the inner patch 142is adhered. Removal of the release layer 140 is facilitated by a slit152 extending from an outer edge of the release layer to the opening150.

The inner patch 142 includes an active agent layer 154 which may be amixture of polymeric materials along with the active agent or otheringredients so as to posses pressure-sensitive adhesive properties foradhering the device 136 to the skin or mucosa of a host. However, it isnot a requirement that the active agent layer 154 have adhesiveproperties. In this regard, the top surface of the active agent layer154 can be coated with an active agent permeable adhesive layer 126. Itis also contemplated, although not shown, that the inner patch 142 mayinclude a rate-controlling polymer layer to provide a means forcontrolling the rate at which the active agent is released from thesurface of the inner patch 142 to the skin or mucosa of the host. Therate-controlling polymer layer may be adhered to the surface of theactive agent layer 154 using any suitable active agent permeableadhesive such as that used for adhesive layer 126.

The inner patch 142 further includes an active agent impermeable backinglayer 156 adhered to the bottom surface of the active agent layer 154.The impermeable backing layer 156 may be adhered using thepressure-sensitive adhesive properties of the active agent layer 154, orby a layer, not shown, of preferably an active agent impermeableadhesive. The release layer 144, similar to release layer 108, isreleasably adhered to the top surface of the inner patch 142 forpreventing release of the active agent and for protecting and preventingcontamination to the adhesive properties of the inner patch.

A portion of the release layer 140 is interposed between a portion ofthe bottom surface of the inner patch 142 and the top surface of theadhesive layer 146 of the outer patch 138. The inner patch 142 is formedwith an annular flap circumscribing the opening 150 of the release layer140 which is isolated from the adhesive layer 146 by the release linerto prevent migration of the active agent therebetween. Upon removal ofthe release layer 140, an annular portion of the top surface of theadhesive layer 146 is exposed surrounding the perimeter of the innerpatch 142. The adhesive layer 146 provides sufficient adhesion to adherethe device 136 to the skin or mucosa of a host. The adhesion of thedevice 136 is enhanced by the inner patch 142 having eitherpressure-sensitive adhesion properties or the incorporation of an activeagent permeable adhesive layer 126. However, it is contemplated that theinner patch 142 will be devoid of adhesive properties, relying solelyupon the adhesive properties of the outer patch 138 to provide adhesionof the device 136 to the skin or mucosa of a host.

As previously described, the active agent or drug is contained withinthe active agent layer 122, 154, and optionally in the adhesive layer110, 146. The active agent may be, for example, systemic or topicaldrugs. Individual active agents or mixtures thereof, if desired, can beemployed. Any drug which passes through the skin or mucosa of a host canbe employed for internal administration in the device of the inventionso long as the drug will pass through the permeable adhesive layer orlayers present. The active agent and thermoplastic matrix polymer can bemelt-blended in an extruder and then formed into the active agent layer122, 154 or adhesive layer 110, 146 by extrusion. Other known processesfor incorporation of the active agent such as solvent blending arecontemplated.

Suitable systemic drugs for administration by the devices of the presentinvention include psychoactive agents such as nicotine, caffeine,mesocarb, mefexamide, cannabinols such as THC, and the like, sedativessuch as diazepam, mepiridine, uldazepam, tybamate, metaclazepam,tetrabarbitol and the like, antidepressants such as amitryptyline,imipramine desipramine, nialamide, melitracen, isocarboxazid, and thelike, anticonvulsants such as phenobarbitol, carbamazepine,methsuximide, 2-ethyl-2-phenylmalonamide (PEMA), phenytoin and the like,steroids such as progesterone, testosterone, pregnanediol, progestin,estradiol, anabolic steroids and the like, analgesics, includingnarcotic analgesics such as codeine, morphine, fentanyl, analorphine,demeral and the like, and analgesics such as acetaminophen, aspirin, andthe like, antimicrobial agents such as sulconazole, siccanin, silversulfadiazine, bentiacide, and the like, tranquilizers such asalprazolam, meprobamate and the like, antineoplastic agents such assulfosfamide, rufocromomycin and the like, and antibiotic agents such astetracycline, penicillin, streptozcin and the like.

The quantity of active agent present is that quantity sufficient toprovide a pharmaceutically or physiologically effective dosage rate ofthe active agent to a host in need thereof. This quantity can be readilydetermined by those of ordinary skill in the art without undueexperimentation as shown in the examples set forth below.

The device 100, 136 of the present invention optionally include arate-controlling polymer layer. The polymers suitable for use as therate-controlling polymer layer are conventional in the art and need notbe discussed in detail here. Some preferred materials include, forexample, polyethylene, polypropylene, ethylene vinyl acetate copolymer(EVA), copolyesters (e.g., HYTREL) and polyurethanes.

The rate of permeation of the active agent through the rate-controllingpolymer layer depends on factors such as the affinity of the activeagent for the polymer layer, molecular size of the active agent,polymeric structure of the carrier layer and the thickness of the layer.Therefore, the appropriate rate-controlling polymeric material and itsthickness depend on the active agent used and the desired rate ofpermeation. The selection of a polymer layer and its thickness providesa means, if desired, for controlling the dosage rate to the skin ormucosa.

Further, an enhancer to promote the penetration of the active agentthrough the skin may be included in either the active agent layers 122,154, rate-controlling polymer layers or the active agent permeableadhesive layers, if present. The enhancer may be incorporated into theselayers by solvent blending or, more preferably, by melt-blending by thesame process utilized to incorporate the active agent into either theactive agent layers 122, 154 or the adhesive layers 110, 146, whichadhesive layers may also include an enhancer.

Suitable enhancers include those described in U.S. Pat. No. 4,573,996,such as the following enhancers: monovalent, saturated and unsaturatedaliphatic and cycloaliphatic alcohols having 6 to 12 carbon atoms suchas cyclohexanol, lauryl alcohol and the like; aliphatic andcycloaliphatic hydrocarbons such as mineral oils; cycloaliphatic andaromatic aldehydes and ketones such as cyclohexanone; N,N-di (loweralkyl) acetamides such as N,N-diethyl acetamide, N,N-dimethyl acetamide,N-(2-hydroxyethyl) acetamide, and the like; aliphatic and cycloaliphaticesters such as isopropyl myristate and lauricidin; N,N-di (lower alkyl)sulfoxides such as decylmethyl sulfoxide; essential oils; nitratedaliphatic and cycloaliphatic hydrocarbons such asN-methyl-2-Pyrrolidone, Azone; salicylates, polyalkylene glycolsilicates; aliphatic acids such as oleic acid and lauric acid, terpenessuch as cineole, surfactants such as sodium lauryl sulfate, siloxanessuch as hexamethyl siloxane; mixtures of the above materials; and thelike.

The backing layer 124, 156 is preferably made of a material orcombination of materials that is substantially impermeable to the layeror layers with which it can be in contact, e.g., to the active agentlayers 122, 154, the adhesive layer 110, 146 and the active agents oringredients contained therein, the adhesives, etc. In this regard, aprimary objective is to prevent migration or seepage of the activeagents or ingredients through the backing layer 124, 156 of the innerpatch 106, 142 into the underlying adhesive layer 110, 146. The backinglayer 112, 148 may also be made from a similar material beingimpermeable to the active agents, particularly when the active agentsare present also within the adhesive layer 110, 146. The backing layer112, 148 is not required to be impermeable to the active agents,particularly when there are no active agents in the adhesive layer 110,146. Thus, it is not necessary in all instances that the backing layer112, 148 be impermeable to the active agents, although in most instancesit normally is.

By impermeable, it is meant that the other components in contact withthe backing layer or component under consideration will not appreciablypermeate through such layer or component for the normal period of useand storage of the device. Some suitable materials for the backing layerinclude, for example, cellophane, cellulose acetate, ethyl cellulose,plasticized vinyl acetate-vinyl chloride copolymers, ethylene-vinylacetate copolymer, polyethylene terephthalate, polyvinyl chloride,nylon, polyethylene, polypropylene and polyvinylidene chloride (e.g.,SARAN).

Examples of suitable pressure-sensitive-adhesive materials for use inthe present invention as an active agent impermeable adhesive includesome natural rubber and synthetic rubber adhesives and cross-linkablelaminating adhesives. Examples of suitable natural rubber adhesivesinclude R-1072 from B.F. Goodrich Co., No. 735 from C.L. Hathaway, andNo. 5702 from Evans St. Clair. Examples of synthetic rubber adhesivesinclude Jowatherem 270-00 and Jowatherem S-3202 from Jowat Corp. and70-9416 from National Starch. Other suitable laminating adhesivesinclude the Dow Corning laminating silicone adhesives and the LordCorporation Tycel 7900 series laminating adhesives. Also contemplatedare acrylic copolymers such as those available from National Starch andChemical Co. of Bridgewater, New Jersey under the marks DURO-TAK 87-2516and DURO-TAK 87-2287. The adhesives most impermeable to most activeingredients are cross-linkable laminating adhesives, which arewell-known to those of ordinary skill in the art.

The active agent permeable adhesive layers are preferably apressure-sensitive adhesive. Any of the well-known, dermatologicallyacceptable, pressure-sensitive adhesives which permit drug migrationtherethrough can be used in the present invention. Some suitablepermeable adhesives include acrylic or methacrylic resins such aspolymers of alcohol esters of acrylic or methacrylic acids and alcoholssuch as n-butanol, isopentanol, 2-methylbutanol, 1-methyl-butanol,1-methyl-pentanol, 2-methylpentanol, 3-methylpentanol, 2-ethyl-butanol,isooctanol, n-decanol, or n-dodecanol, alone or copolymerized withethylenically unsaturated monomers such as acrylic acid, methacrylicacid, acrylamide, methacrylamides, N-alkoxymethyl acrylamides,N-alkoxymethyl methacrylamides, N-t-butyl-acrylamide, itaconic acid,vinyl acetate, N-branched alkyl maleamic acids wherein the alkyl grouphas 10-24 carbon atoms, glycol diacrylates, or mixtures of thesemonomers; polyurethane elastomers; vinyl polymers such as polyvinylalcohol, polyvinyl ethers, polyvinyl pyrrolidone, and polyvinyl acetate;urea formaldehyde resins; phenol formaldehyde resins, resorcinolformaldehyde resins; cellulose derivatives such as ethylcellulose,methylcellulose, nitrocellulose, cellulose acetate butyrate andcarboxymethylcellulose; and natural gums such as guar, acacia, pectina,starch, destria, gelatin, casein, etc.

Other suitable pressure-sensitive adhesives include polyisobutylenepressure sensitive adhesives, rubber pressure-sensitive adhesives andsilicone pressure-sensitive adhesives. The adhesives may also becompounded with tackifiers and stabilizers as is well-known in the art.

Adhesives that are preferred for their active agent permeability includeacrylic copolymer adhesives such as Avery Chemical Company's AS-351 HSX,preferably at a coating weight of between 75 and 125 g/m². Thispressure-sensitive adhesive is a cross-linkable polymer which provides apermanently tacky film having a total solids content of about 52%,Brookfield viscosity (LVT/Spindle No. 4/12 RPM @ 25{grave over ( )}C) offrom about 15,000 to 25,000 cps. at a weight per gallon of about 7.4lbs. It can also be diluted with hexane or toluene to a desired solidsand/or viscosity range, particularly for use in conventional coatingequipment.

Other such adhesives that can also be used for these purposes include anacrylic pressure-sensitive adhesive sold by National Starch and ChemicalCo. under the designation DURO-TAK 80-1054. This adhesive has a solidscontent of 47.5%, a viscosity of 3,000 cps., and plasticity (Williams)of 2.9 mm. It is generally used with a solvent system including ethylacetate, heptane, isopropyl alcohol and toluene. Another such adhesiveis sold by the UCB Group under the designation GELVA MultipolymerEmulsion 2484, and comprises a stable aqueous acrylic emulsionpressure-sensitive adhesive having a solids content of 59% and aviscosity of 1,500 to 2,300 cps. Examples of other acrylic adhesivesinclude Gelva 788 and 733 from UCB, PS-41 from C.L.-Hathaway, Vr-0833from H.B. Fuller, Adcot 73A207A from Morton Chemical, Nos. 80-2404,80-1054, 72-9056 and 72-9399 from National Starch, Nos. E-2015, E-2067and E-1960 from Rohm & Haas, M-6112 from Uniroyal, Inc. and Daratak 74 Lfrom W.R. Grace. Suitable rubber adhesives include Duro-Tak 36-6172 fromNational Starch and Morstik 118 from Morton Chemical. An example of asuitable silicone adhesive is 7-4502 from Dow Corning.

The width (i.e., surface area) and thickness of the permeable adhesivelayer for contact with the skin or mucosa is that width and thicknesswhich provides sufficient permeability to the active agent or activeagent enhancer and a suitable surface area to allow the dosage ratedesired to the skin or mucosa. These widths and thicknesses areconventional in the art and therefore need not be discussed in detailhere.

The active agent layers 122, 154 are preferably monolithic polymericactive agent carrier layers. Thus, in essence, these monolithic activeagent carrier layers basically comprise a thermoplastic polymeric matrixwhich are admixed via melt-blending with the active agent or drugcomponent or active agent enhancer, or both. However, monolithic polymermatrix carrier layers which blend the active agent with a matrix polymerin a common solvent and then evaporate the solvent to form a plasticfilm are contemplated. As is readily understood by those of ordinaryskill in the art, the step of melt-blending requires the use of athermoplastic polymer, that is, one that softens and melts when exposedto heat and then returns to its original condition when cooled. Suitablethermoplastic matrix polymers are the thermoplastic polyurethanes. Ofthis class, the polyether polyurethanes are preferred. These includesuch commercial polyurethane compositions such as Dow Chemical Company'sPELLETHANE, including its 2363-80 AE grade thereof; K.J. Quin's Q-THANE;B.F. Goodrich's ESTANE; Mobay Chemical Company's TXIN; and others.

Suitable thermoplastic matrix polymers also include various polyesters,such as the copolymers of various cyclic polyesters including DuPont'sHYTREL, including its 4056 grade thereof, and General Electric's LOMODboth of which are copolymers of polyether prepolymers and polybutyleneterephthalate and polyisobutylene terephthalate, respectively, as wellas Eastman Chemical's PCCE. Other suitable polymers include ethylenemethacrylic and acrylic acid copolymers. For example, ethylenemethacrylic acid having the commercial designation NUCREL 699 isparticularly suitable as a thermoplastic matrix polymer.

The device 100, 136 include a release liner attached to the device suchas at the surfaces to be adhered to the skin or mucosa of a host. Therelease liner may be made of the same materials suitable for use in thebacking layer provided they are active agent impermeable. Such materialsas a release liner are made removable or releasable from the adhesivelayers or active agent layers by, for example, conventional treatmentwith silicon, Teflon or other suitable coating on the surface thereof.The removal of the device 100, 136 from the release liner may also beprovided by mechanical treatment of the protective layer, e.g., byembossing the protective liner.

The various layers of the device 100, 136 of the present invention maybe combined to form a laminate by methods conventional in the art. Onesuch process includes combining the active agent and a thermoplasticmatrix polymer by melt-blending the two components forming the polymerlayers by extrusion. Another known process is referred to as asolvent-blend process using solvated components which form an admixturethat is coated onto a substrate such as a release liner and subsequentlydried. The melt-blending process is described in further detail in U.S.Pat. No. 6,010,715, the disclosure of which is incorporated herein byreference.

There is also known various materials for use in the construction of thedevice 100, 136 of the present invention for the backing layers, releaselayers, adhesive layers, active agent layers, pressure-sensitiveadhesive layers, active agent permeable adhesive layers, active agentimpermeable adhesive layers, active agent impermeable layers, activeagent permeable adhesive layers, etc. Suitable materials are disclosedin U.S. Pat. Nos. 5,064,422, 5,123,900, 5,503,844 and 5,948,433, thedisclosures of which are incorporated herein by reference.

Referring to FIGS. 8-10, there is illustrated one example of a method ofmanufacturing the device 100, 136 via a solvent-blending process. Withreference to the device 100, the active agent layer 122 is formed byadmixing solvated polymer materials such as those havingpressure-sensitive adhesive properties in conjunction with the activeagent to be administered to the skin or mucosa of a host. The activeagent polymeric admixture is coated onto a release liner, dried,laminated with an active agent impermeable backing layer, and wound intoa continuous supply roll 160. The release liner is separated from theactive agent layer and back slit to form slit 132 while the active agentlayer is die cut to the desired size and shape of the inner patch 106.The release liner and active agent layer are re-joined, followed byremoval of the extraneous active agent layer.

In a similar solvent-blending process as shown in FIG. 9, thepressure-sensitive adhesive matrix materials forming the adhesive layer110 are coated onto a release liner, dried, laminated with a backinglayer, and wound to form a supply roll 162. The release liner is removedfrom the adhesive layer, die cut to form opening 114 and back slit toform slit 120. The release liner is re-joined with the adhesive layer,followed by the removal of the waste adhesive layer.

Referring to FIG. 10, the supported active agent layer 122 is alignedoverlying and in registration with the supported adhesive layer 110, andadhered thereto through the opening in the release liner in a continuousprocess. The release liner for the active agent layer is cut toappropriate size and shape, followed by a guillotine process forsevering the outer patch release layer to form the completed device 100.

It is to be understood that the above description of a method of makingthe device 100, 136, as described with reference to FIGS. 8-10, is byway of one illustrative example only. In this regard, it is contemplatedthat other methods for manufacturing the device 100, 136 arecontemplated, and accordingly, the described method is not to beinterpreted as any limitation upon the scope of the present invention.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

The invention claimed is:
 1. A storage-stable device for the release ofan active agent to the skin or mucosa of a host, said device consistingof: an outer patch having adhesive properties; an inner patch comprisingan active agent layer containing an active agent and a coextensiveactive agent impermeable layer supporting the active agent layer, theactive agent impermeable layer having a first surface in contact withthe active agent layer and a second surface opposing the first surface;and, a release liner interposed between the inner patch and the outerpatch, the release liner releasably adhered to a first adhesive portionof the outer patch and having an opening exposing a second adhesiveportion of the outer patch to the inner patch, wherein, prior to removalof the release liner for application of the device to the skin or mucosaof a host, a portion of the second surface of the active agentimpermeable layer is adhered to the second adhesive portion of the outerpatch exposed by the opening in the interposed release liner, and aremaining portion of the second surface of the active agent impermeablelayer is unadhered to the first or second adhesive portion of the outerpatch as a result of the release liner being interposed therebetweenprior to the removal of the release liner for the application of thedevice; and, the outer patch having a surface area greater than thesurface area of the inner patch, such that removal of the release linerfor the application of the device adheres the remaining portion of theactive agent impermeable layer to the adhesive layer of the outer patchand exposes another adhesive portion of the outer patch extending beyondthe periphery of the inner patch for adhering the device to the skin ormucosa of a host; and a second release liner releasably adhered to saidinner patch.
 2. The device of claim 1, wherein said release linercomprises an active agent impermeable material.
 3. The device of claim1, wherein said inner patch comprises pressure-sensitive adhesivematerial in contact with said active agent layer for adhering saiddevice to the skin or mucosa of a host.
 4. The device of claim 3,wherein said pressure-sensitive adhesive material comprises a layer ofactive agent permeable adhesive applied overlying said active agentlayer of the inner patch for adhering said device to the skin or mucosaof a host.
 5. The device of claim 1, wherein at least one portion ofsaid outer patch includes an active agent to be administered to the skinor mucosa of a host.
 6. The device of claim 1, wherein said active agentis an analgesic.
 7. A storage-stable device for the release of an activeagent to the skin or mucosa of a host, the device consisting of: anouter patch including a backing layer and an adhesive layer supported onthe backing layer; a release liner coextensively and releasably adheredto the adhesive layer of the outer patch, the release liner having anopening exposing therethrough a portion of the adhesive layer; an innerpatch comprising an active agent impermeable layer and an active agentlayer containing an active agent supported on the active agentimpermeable layer, the active agent impermeable layer having a firstportion adhered to the exposed portion of the adhesive layer through theopening in the release liner and a remaining portion of the active agentimpermeable layer being separated from the adhesive layer of the outerpatch by the release liner interposed between the active agentimpermeable layer and the adhesive layer, whereby the first portion ofthe active agent impermeable layer is adhered to the adhesive layer ofthe outer patch prior to removal of the release liner for application ofthe device to the skin or mucosa of the host, and the remaining portionof the active agent impermeable layer is unadhered to the adhesive layerof the outer patch prior to the removal of the release liner forapplication of the device; the inner patch having a surface area smallerthan the surface area of the outer patch, wherein removal of the releaseliner adheres the remaining portion of the active agent impermeablelayer to the adhesive layer of the outer patch and exposes a peripheralportion of the adhesive layer of the outer patch for adhering the deviceto the skin or mucosa of the host with the active agent layer in contactwith the skin or mucosa of the host for administration of the activeagent.